Antibodies specific to human t-cell immunoglobulin and ITIM domain (TIGIT)

Abstract

Natural killer (NK) cell killing of various tumors is inhibited in the presence of ligands of TIGIT, an inhibitory receptor present on all human NK cells and on various T cells. Monoclonal antibodies that recognize TIGIT and inhibit its suppressive activity on T-cells are provided as well as pharmaceutical compositions comprising them and methods for their use in cancer immunotherapy and in diagnosis and treatment of immune disorders.

The invention claimed is: 
     
       1. A polynucleotide comprising a sequence encoding the heavy and light chain variable regions of a monoclonal antibody or a fragment thereof, or a first polynucleotide and a second polynucleotide that comprise sequences encoding the heavy chain variable region and the light chain variable region, respectively, of the monoclonal antibody or fragment thereof, wherein the monoclonal antibody or fragment thereof is capable of binding to human T-cell immunoglobulin and ITIM domain (TIGIT), wherein the antibody fragment comprises at least the antigen binding portion of the monoclonal antibody, and wherein the antibody or fragment thereof is selected from the group consisting of:
 (i) an antibody or fragment thereof comprising six complementarity determining regions (CDRs), wherein the heavy chain (HC) CDR1 comprises the sequence GYTFTSYGIS (SEQ ID NO:1) or TSYGIS (SEQ ID NO:11); the HC CDR2 comprises the sequence: EIYPRSGNTYYNEKFKG (SEQ ID NO:2); the HC CDR3 comprises the sequence: KGPYYTKNEDY (SEQ ID NO:3); the light chain (LC) CDR1 comprises the sequence: RASEHIYYSLA (SEQ ID NO:4); the LC CDR2 comprises the sequence: NANSLED (SEQ ID NO:5); and the LC CDR3 comprises the sequence: KQAYDVPRT (SEQ ID NO: 6); and 
 (ii) an antibody or fragment thereof comprising six CDRs, wherein the HC CDR1 comprises the sequence IYCIH (SEQ ID NO:12); the HC CDR2 comprises the sequence: EISPSNGRTIYNEKFKN (SEQ ID NO:13); the HC CDR3 comprises the sequence: SDGYDGYYFDY (SEQ ID NO:14); LC CDR1 comprises the sequence: RASQEISGYLN (SEQ ID NO:15); the LC CDR2 comprises the sequence: AASTLDS (SEQ ID NO:16); and the LC CDR3 comprises the sequence: LQYASYPRT (SEQ ID NO:17). 
 
     
     
       2. The polynucleotide or the first and the second polynucleotides of  claim 1 , wherein the polynucleotide or the first polynucleotide comprises the sequence set forth in SEQ ID NO:9, or a variant thereof having at least 90% identity to SEQ ID NO:9, encoding the heavy chain variable region of the monoclonal antibody or fragment thereof. 
     
     
       3. The polynucleotide or the first and the second polynucleotides of  claim 1 , wherein the polynucleotide or the second polynucleotide comprises the sequence set forth in SEQ ID NO: 10, or a variant thereof having at least 90% identity to SEQ ID NO:10, encoding the light chain variable region of the monoclonal antibody or fragment thereof. 
     
     
       4. The polynucleotide or the first and the second polynucleotides of  claim 1 , wherein the polynucleotide or the first polynucleotide comprises the sequence set forth in SEQ ID NO:20, or a variant thereof having at least 90% identity to SEQ ID NO:20, encoding the heavy chain variable region of the monoclonal antibody or fragment thereof. 
     
     
       5. The polynucleotide or the first and the second polynucleotides of  claim 1 , wherein the polynucleotide or the second polynucleotide comprises the sequence set forth in SEQ ID NO:21, or a variant thereof having at least 90% identity to SEQ ID NO:21, encoding the light chain variable region of the monoclonal antibody or fragment thereof. 
     
     
       6. The polynucleotide or the first and the second polynucleotides of  claim 1 , wherein the polynucleotide or the first polynucleotide comprises a sequence encoding the amino acid sequence of the heavy chain variable region of the monoclonal antibody or fragment thereof as set forth in SEQ ID NO: 7. 
     
     
       7. The polynucleotide or the first and the second polynucleotides of  claim 1 , wherein the polynucleotide or the second polynucleotide comprises a sequence encoding the amino acid sequence of the light chain variable region of the monoclonal antibody or fragment thereof as set forth in SEQ ID NO:8. 
     
     
       8. The polynucleotide or the first and the second polynucleotides of  claim 1 , wherein the polynucleotide or the first polynucleotide comprises a sequence encoding the amino acid sequence of the heavy chain variable region of the monoclonal antibody or fragment thereof as set forth in SEQ ID NO: 18. 
     
     
       9. The polynucleotide or the first and the second polynucleotides of  claim 1 , wherein the polynucleotide or the second polynucleotide comprises a sequence encoding the amino acid sequence of the light chain variable region of the monoclonal antibody or fragment thereof as set forth in SEQ ID NO:19. 
     
     
       10. The polynucleotide or the first and the second polynucleotides of  claim 1 , wherein the monoclonal antibody or fragment thereof is selected from the group consisting of: a bispecific antibody, a humanized antibody, and an antibody conjugate. 
     
     
       11. The polynucleotide or the first and the second polynucleotides of  claim 10 , wherein the monoclonal antibody or fragment thereof is a bispecific antibody comprising two sets of CDR sequences, wherein:
 one CDR set comprises an HC CDR1 having the sequence GYTFTSYGIS (SEQ ID NO:1) or TSYGIS (SEQ ID NO: 11); an HC CDR2 having the sequence: EIYPRSGNTYYNEKFKG (SEQ ID NO:2); an HC CDR3 having the sequence: KGPYYTKNEDY (SEQ ID NO:3); an LC CDR1 having the sequence: RASEHIYYSLA (SEQ ID NO:4); an LC CDR2 having the sequence: NANSLED (SEQ ID NO:5); and an LC CDR3 having the sequence: KQAYDVPRT (SEQ ID NO:6); and 
 a second set comprises an HC CDR1 having the sequence: IYCIH (SEQ ID NO:12), an HC CDR2 having the sequence: EISPSNGRTIYNEKFKN (SEC ID NO:13), an HC CDR3 having the sequence: SDGYDGYYFDY (SEC ID NO:14), an LC CDR1 having the sequence: RASQEISGYLN (SEC ID NO: 15), an LCCDR2 having the sequence: AASTLDS (SEQ ID NO: 16), and an LC CDR3 having the sequence: LQYASYPRT (SEC ID NO:17). 
 
     
     
       12. A cell comprising the polynucleotide or the first and the second polynucleotides according to  claim 1 . 
     
     
       13. The cell of  claim 12 , wherein the cell is a hybridoma cell. 
     
     
       14. A plasmid comprising the polynucleotide or the first and the second polynucleotides according to  claim 1 . 
     
     
       15. The plasmid of  claim 14 , comprising a polynucleotide sequence set forth in SEQ ID NO:9, SEQ ID NO:20, or both. 
     
     
       16. The plasmid of  claim 14 , comprising a polynucleotide sequence set forth in SEQ ID NO: 10, SEQ ID NO:21, or both.